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FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance

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Title: FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance
Authors: Khongkow, P
Karunarathna, U
Khongkow, M
Gong, C
Gomes, AR
Yague, E
Monteiro, LJ
Kongsema, M
Zona, S
Man, EPS
Tsang, JW-H
Coombes, RC
Wu, K-J
Khoo, U-S
Medema, RH
Freire, R
Lam, EW-F
Item Type: Journal Article
Abstract: FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and mouse embryonic fibroblasts (MEFs) into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an forkhead response element on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7EpiR cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ataxia-telangiectasia mutated (ATM)phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7EpiR cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated homologous recombination (HR) DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence.
Issue Date: 21-Oct-2013
Date of Acceptance: 16-Sep-2013
URI: http://hdl.handle.net/10044/1/39233
DOI: http://dx.doi.org/10.1038/onc.2013.457
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 4144
End Page: 4155
Journal / Book Title: Oncogene
Volume: 33
Issue: 32
Copyright Statement: This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C37/A12011
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
GENETICS & HEREDITY
ONCOLOGY
FOXM1
senescence
DNA damage
NBS1
epirubicin
resistance
breast cancer
DOUBLE-STRAND BREAKS
ATR-DEPENDENT PHOSPHORYLATION
MRE11-RAD50-NBS1 COMPLEX
MAMMALIAN-CELLS
CANCER CELLS
EXPRESSION
REPAIR
ACTIVATION
PATHWAY
LINKAGE
Animals
Antibiotics, Antineoplastic
Cell Aging
Cell Cycle Proteins
DNA Damage
DNA Repair
Drug Resistance, Neoplasm
Epirubicin
Fibroblasts
Forkhead Transcription Factors
Gene Deletion
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
MCF-7 Cells
Mice
Nuclear Proteins
Phenotype
Phosphorylation
Promoter Regions, Genetic
Signal Transduction
Fibroblasts
Animals
Humans
Mice
DNA Damage
Epirubicin
Cell Cycle Proteins
Nuclear Proteins
Antibiotics, Antineoplastic
Cell Aging
Signal Transduction
DNA Repair
Gene Expression Regulation, Neoplastic
Gene Silencing
Gene Deletion
Phosphorylation
Drug Resistance, Neoplasm
Phenotype
Forkhead Transcription Factors
Promoter Regions, Genetic
MCF-7 Cells
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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